Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances

Table 1 Ongoing clinical trials investigating immune checkpoint inhibitor - oral tyrosine kinase inhibitor combinations

NCT	Phase	Study drugs	Treatment line	Endpoint	Estimated End of Trial
NCT04194775	3	CS1003 +LENVATINIB vs LENVATINIB	1	OS, PFS	June 2023
NCT04344158	3	PENPULIMAB + ANLOTINIB vs SORAFENIB	1	OS	December 2024
NCT03713593	3	PEMBROLIZUMAB + LENVATINIB vs LENVATINIB	1	OS, PFS	May 2022
NCT04411706	2	SINTILIMAB + APATINIB + CAPECITABINE	1	ORR	June 2022
NCT04042805	2	SINTILIMAB + LENVATINIB	1	ORR	August 2024
NCT04444167	2	BISPECIFIC AK104 + LENVATINIB	1	ORR	March 2022
NCT04183088	2	TISLELIZUMAB + REGORAFENIB	1	ORR, PFS, Safety	March 2025
NCT04310709	2	NIVOLUMAB + REGORAFENIB	1	ORR	May 2023
NCT04442581	2	PEMBROLIZUMAB + CABOZANTINIB	1	ORR	September 2024
NCT03439891	2	NIVOLUMAB + SORAFENIB	1	MTD, ORR	May 2022
NCT04170556	2	NIVOLUMAB + REGORAFENIB	2	Safety	December 2022
NCT04401800	1b/2	TISLELIZUMAB + LENVATINIB	1	ORR	December 2022
NCT04443309	1b/2	CAMRELIZUMAB + LENVATINIB	1	ORR	August 2024
NCT03347292	1	PEMBROLIZUMAB + REGORAFENIB	1	DLT, Safety	October 2022

NCT: Number of the clinical trial (Clinicaltrials.gov); OS: Overall survival; PFS: Progression-free survival; ORR: Overall response rate; MTD: Maximum tolerated dose; DLT: Dose-limiting toxicities.

Table 2 Ongoing clinical trials investigating combinations of immune checkpoint inhibitors and anti-vascular endothelial growth factors factors

NCT	Phase		Study drugs	Treatment line	Endpoint	Estimated End of Trial
NCT03794440		2/3	SINTILIMAB + BEVACIZUMABBIOSIMILAR	1	OS, ORR	December 2022
NCT03970616		1b/2	DURVALUMAB + TIVOZANIB	1	Safety	August 2022
NCT03973112		2	HLX-10+BEVACIZUMAB BIOSIMILAR	1	ORR	June 2022

NCT: Number of the clinical trial (Clinicaltrials.gov); OS: Overall survival; ORR: Overall response rate.

Table 3 Ongoing clinical trials investigating combinations of locoregional therapy and immune checkpoint inhibitors

NCT	Phase	Locoregional Therapy	Systemic Therapy	Endpoint	Estimated End of Trial
NCT03817736	2	TACE + SBRT	ICI	Sequential	February 2024
NCT03638141	2	DEB-TACE	DURVALUMAB + TREMELIMUMAB	Sequential	November 2023
NCT03143270	1	TACE	NIVOLUMAB	Combination	April 2022
NCT03572582	2	TACE	NIVOLUMAB	Combination	June 2023
NCT03397654	1/2	TACE	PEMBROLIZUMAB	Sequential	December 2021 (results awaited)
NCT03383458	3	Curative resection or ablation	NIVOLUMAB	Adjuvant	June 2025
NCT02821754	2	TACE, RFA, Cryo	DURVALUMAB, TREMELIMUMAB	Combination	December 2022
NCT03033446	2	Y90-Radioembolization	NIVOLUMAB	Combination	December 2021 (results awaited)
NCT03099564	1	Y90-Radioembolization	PEMBROLIZUMAB	Combination	July 2022
NCT03259867	2	TATE	NIVOLUMAB OR PEMBROLIZUMAB	Combination	December 2022
NCT03937830	2	TACE	DURVALUMAB + TREMELIMUMAB + BEVACIZUMAB	Combination	December 2023
NCT03778957	3	TACE	DURVALUMAB or DURVALUMAB + BEVACIZUMAB	Combination	August 2024
NCT04340193	3	TACE	NIVOLUMAB + IPILIMUMAB or NIVOLUMAB MONOTHERAPY or DOUBLE PLACEBO	Combination	January 2024
NCT04246177	3	TACE	PEMBROLIZUMAB + LENVATINIB	Combination	December 2029
NCT04268888	2/3	TACE/TAE	NIVOLUMAB	Combination	June 2026
NCT05162898	N/A	RFA	TORIPALIMAB + LENVATINIB	Combination	December 2025
NCT05057845	2	Cryo	TISLELIZUMAB + LENVATINIB	Combination	September 2024
NCT04988945	2	TACE + SBRT	DURVALUMAB + TREMELIMUMAB	Sequential (for downstaging)	December 2026
NCT04727307	2	RFA	ATEZOLIZUMAB (neoadjuvant) + ATEZOLIZUMAB-BEVACIZUMAB (adjuvant)	Combination	July 2027
NCT04663035	2	Ablation	TISLELIZUMAB	Combination	December 2025
NCT04652440	1/2	RFA	TISLELIZUMAB	Combination	November 2023
NCT04639180	3	Curative resection or ablation	CAMRELIZUMAB + APATINIB	Adjuvant	July 2024
NCT04220944	1	MWA+TACE	SINTILIMAB	Combination	September 2022
NCT04102098	3	Surgical resection or ablation	ATEZOLIZUMAB+ BEVACIZUMAB	Adjuvant	July 2027
NCT03867084	3	Surgical resection or local ablation	PEMBROLIZUMAB	Adjuvant	June 2025
NCT03864211	1/2	Thermal ablation (MWA or RFA)	TORIPALIMAB	Combination	June 2023
NCT03753659	2	MWA or RFA or Brachytherapy or TACE	PEMBROLIZUMAB	Combination	June 2024
NCT03630640	2	Electroporation	NIVOLUMAB (neoadjuvant & adjuvant)	Combination	November 2023

NCT: Number of the clinical trial (Clinicaltrials.gov); TACE: Transarterial chemoembolization; SBRT: Stereotactic body radiotherapy; DEB: Drug eluting bead; RFA: Radiofrequency ablation; Cryo: Cryoablation; TATE: Transarterial tirapazamine embolization; TAE: Transarterial embolization; MWA: Microwave ablation.

Table 4 Ongoing clinical trials investigating immune checkpoint inhibitor - based clinical trials in the adjuvant and neoadjuvant setting

NCT	Phase	Study drugs	Treatment setting	Endpoint	Estimated End of Trial
NCT03383458	3	NIVOLUMAB vs PLACEBO	Adjuvant	RFS	June 2025
NCT03867084	3	PEMBROLIZUMAB vs PLACEBO	Adjuvant	RFS, OS	June 2025
NCT03847428	3	DURVALUMAB + BEVACIZUMAB vs PLACEBO	Adjuvant	RFS	September 2023
NCT04102098	3	ATEZOLIZUMAB + BEVACIZUMAB vs PLACEBO	Adjuvant	RFS	July 2027
NCT03859128	2/3	TORIPALIMAB vs PLACEBO	Adjuvant	RFS	April 2024
NCT03839550	2	CAMRELIZUMAB + APATINIB	Adjuvant	RFS	February 2023
NCT04418401	2	ANTI-PD1 + DONAFINIB	Adjuvant	RFS	June 2023
NCT03510871	2	NIVOLUMAB + IPILIMUMAB	Neoadjuvant	ORR, downstaging rate	December 2022
NCT04123379	2	NIVOLUMAB + CCR2/5-inhibitor vs NIVOLUMAB +ANTI-IL8	Neoadjuvant	Safety	October 2024
NCT03222076	2	NIVOLUMAB	Neoadjuvant	Safety	September 2022
NCT03682276	1/2	NIVOLUMAB + IPILIMUMAB	Neoadjuvant	Safety, Delay to surgery	September 2022
NCT03383458	1	NIVOLUMAB vs PLACEBO	Adjuvant	RFS	June 2025
NCT04425226	N/A	PEMBROLIZUMAB + LENVATINIB	Neoadjuvant	RFS, ORR	December 2025

NCT: Number of the clinical trial (Clinicaltrials.gov); RFS: Recurrence-free survival; OS: Overall survival; RFS: Recurrence-free survival; ORR: Overall response rate.